Many patients with intrathoracic malignancies will receive radiation therapy for the treatment for their disease. This often necessitates exposure of significant portions of their lung to high doses of radiation. One particularly devastating late injury caused by radiation is pulmonary fibrosis. This problem develops as progressive shortness of breath with increasing interstitial lung fibrosis and loss of alveolar structures. The risk of pulmonary fibrosis may limit the volume of irradiation and compromise a potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Stromal cell-derived factor 1 (SDF-1/CXCL12) is a chemokine that through interactions with its receptor CXCR4 may play an important role in the fibrotic response through recruitment of bone marrow-derived progenitor cells to the injured lung. The chemotaxis of these cells to an area of lung injury is believed to be a critical step in the ultimate development pulmonary fibrosis. In mouse models of bleomycin-induced pulmonary fibrosis, inhibitors of CXCR4 can significantly decrease the development of lung fibrosis. We have recently developed an inhibitor of CXCR4 (WZ40) that binds this receptor in the nM range and may induce less toxicity than other currently available CXCR4 antagonists. In our preliminary work, we also find that WZ40 can similarly block bleomycin-induced lung fibrosis. Although the latency period for development of lung fibrosis after radiation exposure is longer than that observed with bleomycin, we hypothesize that radiation-induced fibrosis likely occurs via a similar mechanism to that induced by the lung-toxic chemotherapy and involves recruitment of CXCR4+ bone marrow-derived progenitor cells. Thus, we believe that CXCR4 inhibition will also inhibit pulmonary fibrosis after lung irradiation. In our initial Aim, we plan to determine 1) whether SDF-1 levels are increased after lung irradiation, 2) whether this leads to recruitment of CXCR4+ stem cells which helps drive fibrogenesis, and 3) whether our CXCR4 antagonist WZ40 can block the recruitment of these CXCR4+ stem cells. In our second Aim, we intend to determine whether WZ40 can inhibit the development of radiation-induced pulmonary fibrosis in an established C57BL/6 mouse model. Here, we hope to also establish the optimal dosing regimen for this drug. The primary goal of this study is to determine the potential utility of this new drug in the prevention of radiation-induced pulmonary fibrosis and to hopefully carry it forward in clinical trial for this problem. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to evaluate a new drug for its ability to suppress the development of radiation- induced pulmonary fibrosis. This late effect of radiation therapy may potentially limit the dose and extent of radiation therapy used for thoracic malignancies. If successful, this drug may be carried forward to clinical trial to attempt to prevent this potentially debilitating side effect of radiation treatments.